Statins, the HMG CoA reductase inhibitors, are lipid lowering drugs used to treat cardiovascular disease (CVD), a disease that affects over 64 million Americans and remains the leading cause of death in both sexes and for all major ethnic groups in the U.S. Statins act to reduce blood cholesterol levels by the inhibition of HMG CoA reductase and are the largest single class of drugs prescribed for CVD prevention, with over 120 million prescriptions in 2003. The primary clinical rationale for the use of statins is to reduce the level of LDL-cholesterol and, thereby, to reduce CVD risk. This effect is due in large part to increased LDL and IDL clearance as a result of the up regulation of LDL receptors. Multiple intervention trials with statin drugs have demonstrated a remarkable degree of consistency in their ability to reduce risk for both CVD and stroke by an average of approximately ¼ to ⅓. Moreover, in studies such as the landmark Heart Protection Study, similar benefit has been observed among multiple population subgroups, including men and women, older vs. younger individuals, diabetic vs. nondiabetic subjects, and individuals with a range of baseline CVD risk factors, including elevations in LDL cholesterol as well as other lipids and lipoproteins. Nevertheless, in all of these trials, residual CVD risk remains high (60-75%), and potential drug-related toxicity, while infrequent, is a significant concern, i.e., there is large individual variation in the drug response phenotype after statin therapy.
Several studies, including the Cholesterol/Atherosclerosis Pharmacogenetics (CAP) study have demonstrated a wide range of lipid and lipoprotein responses to statin therapy (J. Simon et al., Phenotypic Predictors of Response to Simvastatin Therapy Among African-Americans and Caucasians: The Cholesterol and Pharmacogenetics (CAP) Study, Am. J. Cardiol. 2006; 97: 843-850). The decrease in LDL cholesterol for a given statin in apparently similar individuals has been found to range from less than 5% to greater than 60%, even when compliance is taken into account. Similar variation has been observed for other statin effects that can contribute to CVD outcomes, including reductions in triglyceride and VLDL, increases in HDL, and reductions in C-reactive protein. Mechanisms for the observed drug response phenotypes remain illusive.
Statin therapy provides outcome benefit to only about 30% of treated individuals (LaRosa et al. JAMA 1999; 282:2340-6). Although statins appear reasonably benign from a safety perspective (with a few notable exceptions), the decision to treat involves some risk (e.g., rhabdomyolysis) and considerable expense to both individuals and to payers. Thus, effective tools for predicting those individuals who will respond to statin therapy would provide benefit to both individuals and the healthcare system. However, because statins are relatively safe and because outcome can be measured from a cholesterol reduction after several weeks of therapy, an effective test should be both accurate and predictive of response shortly after commencing therapy or even from a pre-treatment sample.
The present invention provides methods for predicting responsiveness to statin therapy based on lipidomic analysis.